Voltage-activated sodium (Nav) channels are found throughout the human body where they form the cornerstones of fast electrical signaling by regulating the Na+ permeability ofthe cell membrane. As such, Nav channels are among the most widely targeted ion channels by both drugs and toxins. Their medical relevance is underscored by mutations that underlie debilitating disorders such as epilepsy, muscle weakness, cardiac arrhythmias and pain syndromes. Despite their physiological importance, our understanding of thes;e channels is hampered by a lack of insight into their complex structures and working mechanisms. Rather than existing as independent units, Nav channels are part of a signaling complex that involves auxiliary proteins and membrane lipids. My goal is to address fundamental questions on the identities of the Nav channel signaling complex components and to resolve their mechanisms of action at the molecular level. In particular, I will examine to what extent and by what mechanism auxiliary 3-subunits shape Nav channel gating behavior and pharmacology. Furthermore, I intend to investigate how the surrounding membrane lipids influence Nav channel function and their interaction with (3-subunits. Successful completion of my aims will reveal key elements in the Nav channel signaling complex, help define Nav channel function in normal and pathological states, and may offer novel strategies for developing therapeutic drugs.